With few exceptions, iron is an essential nutrient for all microbes. Under physiological conditions, iron persists predominantly in insoluble ferric (Fe3+) hydroxides and is typically complexed to proteins for transport and storage through animal fluids. Intracellular iron is borne by ferritins, a phylogenetically ubiquitous class of globular iron storage proteins, and by heme associated proteins, while serum iron is bound by glycoproteins, principally transferrin. Enhanced iron sequestration, known as hypoferremia, is a facet of the innate immune response that further restricts iron availability to invading pathogens. This arises from endocytosis of ferrated glycoproteins, an increase in hepatically localized ferritin, and restriction of iron release into the extracellular milieu by the reticuloendothelial system. Owing to its low solubility and stringent sequestration, free iron in human tissues is estimated to be around 10−18 M, well below the threshold required to sustain microbial life, making iron acquisition a major challenge faced by agents of systemic infection.
Numerous bacteria, fungi, and plants overcome iron limitation by secreting siderophores: low molecular weight, high affinity ferrichelators. In mammalian sera, these may compete with transferrin for host iron. Ferrated siderophores are recognized by cognate cell surface receptor proteins and transported through the cytosolic membrane via ATP-binding cassette (ABC) transporters. Siderophore mediated iron uptake makes a significant contribution to the pathogenesis of many Gram-positive and Gram-negative bacterial pathogens, including Yersinia pestis, Burkholderia cepacia, Pseudomonas aeruginosa, septicemic Escherichia coli and Staphylococcus aureus. 
Staphylococcus aureus (S. aureus) is a commensal organism as well as a pathogen of several mammalian species, including humans and cattle. S. aureus isolates that caused infection in cows, horses, goats, sheep and camel have been reported. Isolates of zoonotic S. aureus in which infection has passed from humans to other animals and vice versa have also been reported.
S. aureus is a colonist of human mucosal and epidermal surfaces, and a frequent opportunistic pathogen of surgical wounds and implanted medical devices. S. aureus expresses a myriad array of virulence factors, including adhesins, proteases, lysins, and superantigens, many of which act to improve iron availability through processes such as erythrolysis. Systemic dissemination through blood and soft tissues is characterized by rapid bacterial proliferation and tissue destruction, manifesting in syndromes including septicemia, endocarditis, and necrotizing pneumonia. Coordinated expression of a broad swath of staphylococcal virulence factors takes its cue from iron restriction, a phenomenon mediated by the ferric uptake regulator, Fur. This DNA binding protein recognizes Fe2+ as a repressive cofactor. Plunging levels of soluble iron lead to its dissociation from cognate Fur boxes in operator regions of the iron responsive regulon and derepression of transcription.
S. aureus is a prevalent human pathogen that causes a wide range of infections ranging from minor skin lesions, impetigo and food poisoning to more serious diseases such as sepsis, endocarditis, osteomyelitis, pneumonia, bacteremia, and toxic shock syndrome. Initially, penicillin could be used to treat even the worst S. aureus infections. However, the emergence of penicillin-resistant strains of S. aureus has reduced the effectiveness of penicillin in treating S. aureus infections and most strains of S. aureus encountered in hospital infections today do not respond to penicillin.
Methicillins, introduced in the 1960s, largely overcame the problem of penicillin resistance in S. aureus. However, methicillin resistance has emerged in S. aureus, along with resistance to many other antibiotics effective against this organism, including vancomycin, aminoglycosides, tetracycline, chloramphenicol, macrolides and lincosamides. In fact, methicillin-resistant strains of S. aureus generally are multiply drug resistant. Methicillian-resistant S. aureus (MRSA) has become one of the most important nosocomial pathogens worldwide and poses serious infection control problems. Drug resistance of S. aureus infections poses significant treatment difficulties, which are likely to get much worse unless new therapeutic agents are developed.
Accordingly, it would be desirable to develop novel methods of treating S. aureus infection based on a more thorough understanding of the essential iron-uptake pathways in this organism.